ES2334260T3 - PROCEDURES FOR THE PREPARATION OF THE FORM I CRYSTALINE OF CINACALCET CHLORHYDRATE. - Google Patents

Abstract

Cinacalcet salts substantially free of cinacalcet carbamate, and processes for the preparation thereof.

Description

Procedures for the preparation of form I Cinacalcet hydrochloride crystal.

Field of the Invention

The present invention relates to a procedure intended for the preparation of a crystalline form of hydrochloride (R) -? -Methyl-N- [3- [3- (trifluoromethyl) phenyl] propyl] -1-naphthalenemethane amine.

Background of the invention

(R) -? -Methyl-N- [3- [3- (trifluoromethyl) phenyl] propyl] -1-naphthalenemethane amine (referred to herein as "Cinacalcet" or "CNC") has the CAS number: 226256-56-0, formula C_ {22} H_ {22} F_ {3} N and the following structure:

one

Cinacalcet is the free hydrochloride base of Cinacalcet (here "CNC-HCL"), with CAS number 364782-34-3 and the following structure:

2

CNC-HCL is marketed as SENSIPAR? And was the first FDA-approved drug of a class of compounds known as calcimimetics. The calcimimetics are a class of orally active small molecules which decrease the secretion of parathyroid hormone ("PTH") by activating calcium receptors. The secretion of PTH is normally regulated by the action of the recipient calcium sensitive Calcimimetics increase sensitivity of this receptor to calcium, which inhibits the release of hormone parathyroid and decreases parathyroid hormone levels in a few hours. Calcimimetics are used in the treatment of hyperthyroidism, a disorder characterized by excessive PTH secretion that occurs when calcium receptors in parathyroid glands stop responding properly to calcium in the bloodstream. Elevated levels of PTH, a secondary hyperparathyroidism indicator, are associated with a impaired calcium and phosphorus metabolism, which can cause pain bone, fractures and may increase the risk of death cardiovascular. As calcimimetic, the CNC-HCL is approved for the treatment of secondary hyperparathyroidism in patients with chronic renal disorder undergoing dialysis. He CNC-HCL treatment reduces serum levels of PTH in addition to the ionic calcium / phosphorus product, an indicator of  Amount of calcium and phosphorus in the blood.

Inorganic ionic molecules active in receptors, especially active molecules in calcium receptors, such as those with the general structure of Cinacalcet, are disclosed in US Patent No. 6,011,068. US Patent No. 6,211,244 discloses active compounds in the calcium receptor related to Cinacalcet and processes for the production of said compounds. Cinacalcet and its enantiomer can be produced by multiple procedures, using procedures disclosed in US Patent No. 6,211,244; Drugs of the future, 27 (9): 831 (2002); US Patent No. 5,648,541; No. 4,966,988 and Tetrahedron Letters 45: 8355 (2004), annotation 12.

The present invention relates to physical properties of solid state Cinacalcet hydrochloride. These properties can be influenced by controlling the conditions for obtaining Cinacalcet hydrochloride in the form solid. The solid state physical properties comprise, by example, the fluidity of the ground solid, the dissolution rate in aqueous fluid, compaction behavior and stability  of storage. The discovery of new procedures for the preparation of said polymorphic forms provides opportunities to improve the behavioral characteristics of a pharmaceutical product

The Summary Basis of Approval of New Drug Applications # 21688 published by the FDA mentions that Cinacalcet hydrochloride has only a stable crystalline form at room temperature. However, there are no prior art publications on methods for preparing crystalline Cinacalcet hydrochloride. Accordingly, there is a need in the matter of additional methods of preparing crystalline Cinacalcet hydrochloride.

Summary of the invention

The present invention relates to Preparation procedures of the crystalline form of hydrochloride of Cinacalcet (referred to as Form I) characterized by peaks of X-ray powder diffraction at 13.9, 19.0, 21.3 and 25.5 ± 0.2 2 degrees?

In another embodiment, the present invention comprises a method of preparing the crystalline Form I of Cinacalcet hydrochloride which comprises providing a Cinacalcet base solution in a solvent in which Cinacalcet hydrochloride has low solubility; acidify the solution with hydrochloric acid in order to obtain a reaction mixture; maintaining the reaction mixture to obtain a precipitate, and recovering the crystalline Form I of precipitated Cinacalcet hydrochloride, in which the solvent is selected from the group consisting of water, a C 3 -C 6 ketone a hydrocarbon C 5 -C 8 aliphatic or aromatic, a C 3 -C 6 ester different from ethyl acetate, a C 2 -C 5 alcohol, a C 2 -C_ ether {6}, acetonitrile DMAc, DMF, DMSO, NMP and mixtures of the
same.

In an embodiment of the present invention, the present invention comprises a method of Preparation of the crystalline form I of Cinacalcet hydrochloride which comprises providing a slurry of Cinacalcet hydrochloride amorphous in a solvent selected from the group constituted by water, MTBE and C 5 -C 8 alkanes; keep the grout at a temperature between about temperature ambient and reflux temperature for between 2 and 30 hours and recover the crystalline Form I of Cinacalcet hydrochloride.

In another embodiment, the present invention comprises a method of preparing Form I Cinacalcet hydrochloride crystal comprising providing a solution of Cinacalcet hydrochloride in a solvent selected from among the ketone C 3 -C 8 or linear or branched C 1 -C 5 alcohol, combine the solution with an anti-solvent, maintain the solution in order to obtain a precipitate and recover the crystalline Form I of Cinacalcet hydrochloride.

Brief description of the drawings

Figure 1 illustrates an XRD diffractogram of the Cinacalcet hydrochloride form I crystalline.

Figure 2 illustrates a DSC thermogram of the Cinacalcet hydrochloride form I crystalline.

Figure 3 illustrates a TGA thermogram of the Cinacalcet hydrochloride form I crystalline.

Figure 4 illustrates a diffraction pattern of X-ray powder of amorphous Cinacalcet hydrochloride.

Detailed description of the invention

As used herein, "RT" refers to room temperature and indicates a temperature between about 18 ° C and 25 ° C, preferably between 20ºC and 22ºC.

As used herein, the expression "Cinacalcet hydrochloride Form I crystalline" refers to a crystalline form of Cinacalcet hydrochloride characterized by X-ray diffraction peaks ("XRD") in powder at 13.9, 19.0, 21.3 and 25.5 ± 0.2 degrees 2 ta.

As used herein, "Amorphous Cinacalcet Hydrochloride" refers to a form amorphous Cinacalcet hydrochloride characterized by a pattern of XRD powder substantially as described in Figure 4 and that can be prepared by the procedure disclosed in the US patent applications co-pending 60 / 739,215 and 60 / 742,626.

Cinacalcet hydrochloride crystalline currently marketed as SENSIPAR? is characterized in that it has powder XRD diffraction peaks at 13.9, 19.0, 21.3 and 25.5 ± 0.2 degrees 2 ta. This form crystalline can be further characterized by a pattern XRD powder with peaks at approximately 15.0, 15.5, 16.0, 17.9, 23.7 and 24.3 ± 0.2 degrees 2? Or substantially as described in Figure 1. The differential calorimetry thermogram Tracking ("DSC") of the crystalline form shows two peaks endothermic at between approximately 160ºC and approximately 170ºC and at between 175 ° C and about 185 ° C, substantially as is described in Figure 3. Thermogravimetric analysis ("TGA") in this crystalline form, substantially as described in Figure 4, shows weight losses of less than 1%, therefore this form can be considered anhydrous.

In another embodiment, the present invention comprises a method of preparing Form I Cinacalcet hydrochloride crystal comprising providing a solution of Cinacalcet base in a solvent in which the Cinacalcet hydrochloride has low solubility; acidify the solution with hydrochloric acid in order to obtain a mixture reaction, keep the reaction mixture in order to obtain a precipitate and recover the precipitate from crystalline Form I of Cinacalcet hydrochloride, in which the solvent is selected from among the group consisting of water, ketone C 3 -C 6, aromatic hydrocarbons or C 5 -C 8 aliphatic, ester C 3 -C 6 other than ethyl acetate, C 2 -C 5 alcohol, ether C 2 -C 5, DMAc, DMF, DMSO, NMP and mixtures of the same.

The solvents in which the hydrochloride of Cinacalcet has low solubility comprise, without being limited to these, water, C 3 -C 6 ketone, hydrocarbon aromatic or aliphatic C 5 -C 8, ester C 3 -C 6 different from ethyl acetate, C 1 -C 5 alcohol, ether C 2 -C 5, dimethylacetamide ("DMAc"), dimethylformamide ("DMF"), dimethylsulfoxide ("DMSO"), N-methyl-2-pyrrolidone ("NMP") and mixtures thereof. Preferably, the solvent is selected from the group consisting of water, acetone, n-heptane, n-pentane, ether diethyl, isobutyl acetate, toluene, methyl tert-butyl ether, ("MTBE"), ethanol, DMF, DMSO, NMP, acetonitrile, DMAc, n-pentane, n-hexane, and cyclohexane. More preferably the solvent is selected from the group consisting of water, toluene, acetone and MTBE. The most preferred solvent is MTBE.

Cinacalcet base and solvent are combined to approximately room temperature in at least an amount Enough to get a solution.

The acidification of the mixture can be by gaseous or liquid hydrochloric acid. Preferably, when the solution is acidified with aqueous hydrochloric acid, the amount of acid is enough to react with substantially all of the Cinacalcet base, more preferably an amount comprised between about 1 to 2 moles per mole of Cinacalcet base. The Aqueous solution can be added dropwise or in one portion. Preferably, when the solution is acidified with acid gaseous hydrochloric acid is acidified until it no longer forms precipitate.

Preferably, the reaction mixture obtained by adding hydrochloric acid it is stirred for between approximately 20 minutes and approximately 72 hours.

The crystalline Form I hydrochloride of Cinacalcet can be recovered using any one of the methods known in the art, such as by filtering, washed, preferably with the solvent used, and dried. He drying is preferably carried out until a weight is obtained constant, preferably at a temperature between about 45 ° C and 55 ° C, more preferably at a temperature of about 50 ° C, under reduced pressure.

In an embodiment of the present invention, Cinacalcet hydrochloride Form I crystalline is prepared by a method comprising providing a grout of amorphous Cinacalcet hydrochloride, in a solvent selected from the group consisting of water, MTBE, alkanes C_ {5} -C_ {6}, keep the grout at a temperature between room temperature and reflux temperature for between 2 and 30 hours and recover the Cinacalcet hydrochloride form I crystalline.

Preferably, the solvent is selected from between the group consisting of water, MTBE and n-hexane Preferably, the solvent is used in an amount between approximately 5 and 25 ml per gram of amorphous Cinacalcet hydrochloride.

Preferably, the slurry is maintained for between about 2 hours, more preferably between about 2 and about 24 hours.

The recovery stage may comprise filtered, washed and dried. Drying is preferably performed at reduced pressure, preferably under vacuum, at a temperature between about 40 ° C and about 60 ° C, plus preferably between about 45 ° C and about 50 ° C. Preferably, the product is dried for at least about 5 hours and more preferably, between about 7 hours and approximately 24 hours.

In another embodiment, the present invention comprises a method of preparing Form I Cinacalcet hydrochloride crystal comprising providing a solution of Cinacalcet hydrochloride in a solvent selected from C 3 -_ {6} ketones or C 1 -C 5 linear or branched alcohols, combine the solution with an anti-solvent, keeping the solution in order to obtain a precipitate and recover the Cinacalcet hydrochloride form I crystalline.

Preferably, the solvent is selected from between the group consisting of acetone, ethanol, isopropyl alcohol  ("IPA") and methanol. Preferably, the amount of solvent It is at least sufficient to obtain a solution, preferably the amount is between approximately 3 and approximately 33 ml per gram of hydrochloride from Cinacalcet.

The anti-solvent is a solvent in which the Cinacalcet hydrochloride is poorly soluble. Preferably, the Anti-solvent is selected from the group consisting of water, a cyclic or non-cyclic hydrocarbon C 5 -C 6, aliphatic or branched ethers C 2 -C 5 and mixtures thereof. Plus preferably, the anti-solvent is a solvent in which the Cinacalcet hydrochloride is substantially insoluble, such as water, n-heptane, n-hexane, n-pentane, diethyl ether, MTBE, cyclohexane, or mixtures thereof.

The combination of the solution with the Anti-solvent can be achieved in a single portion or drop by drop. He  Anti-solvent is preferably added in an amount comprised between approximately 4 volumes and approximately 100 volumes of dissolution. The reaction mixture obtained after the addition of the anti-solvent is preferably stirred for at least about 10 minutes, more preferably between approximately 10 minutes and approximately 24 hours.

Cinacalcet Hydrochloride Form I can be recovered by any of the procedures known in the art, such as by filtering, washing, preferably with the solvent used and dried. The drying is preferably performed until a constant weight is obtained, preferably at a temperature between 45 ° C and about 55 ° C, more preferably at a temperature of approximately 50 ° C, under reduced pressure.

Having described the present invention with reference to certain preferred embodiments, other forms of realization will be evident to those skilled in the art to from the consideration of the specification.

The present invention is further defined referring to the following examples that describe with detail the preparation procedures of the present invention. It will be apparent to those skilled in the art that can be make many modifications, both in the materials and in the procedures, without departing, therefore, from the scope of this invention.

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Examples Preparation of Form I crystalline hydrochloride Cinacalcet from amorphous Cinacalcet hydrochloride Example 1

A 0.5 gram slurry of Amorphous Cinacalcet Hydrochloride in 4 ml of water at the temperature of  reflux for 23.5 hours and then cooled to temperature ambient. The product was isolated by filtration, washed with 2 ml of water and dried at 50 ° C in a vacuum oven for 23 hours, providing 0.43 grams of crystalline Form I hydrochloride from Cinacalcet.

Example 2

A slurry of 0.3 g of hydrochloride was stirred Amorphous Cinacalcet in 4 ml of MTBE at room temperature for 18.5 hours The product was isolated by filtration, washed with 2 ml of MTBE and dried at 50 ° C in a vacuum oven for 7 hours, providing 0.26 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 3

A slurry of 0.3 g of hydrochloride was stirred Cinacalcet in 6 ml of MTBE at reflux temperature for 2 hours, cooled to room temperature and stirred at temperature ambient for an additional 16 hours. The product was isolated by filtration, washed with 4 ml of MTBE and dried at 50 ° C in an oven empty for 7 hours, providing 0.19 g of Form I Cinacalcet hydrochloride crystal.

Example 4

A slurry of 0.3 g of hydrochloride was stirred Cinacalcet amorphous in 6 ml of n-hexane reflux temperature for 4 hours and then cooled to room temperature. The product was isolated by filtration, washed with 5 ml of n-hexane and dried at 45 ° C in an oven empty for 15 hours, providing 0.23 g of Form I Cinacalcet hydrochloride crystal.

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Preparation of Form I crystalline hydrochloride Cinacalcet from Cinacalcet base Example 5

A base solution of Cinacalcet was produced by dissolving 1.0 g of Cinacalcet base in 4 ml of absolute ethanol Then, 15 ml of 1 N hydrochloric acid ("HCl") to the solution. Mix resulting was stirred at room temperature for 20 hours, generating a precipitate. The product was isolated by filtration, it was washed with 6 ml of water and dried in a vacuum oven at 50 ° C for 24 hours, producing 0.97 g of Cinacalcet hydrochloride. He Final product was analyzed by powder XRD. The diffractogram of resulting powder illustrated in Figure 2, shows that the product is Form I hydrochloride crystalline hydrochloride Cinacalcet

Example 6

0.93 g of Cinacalcet base was dissolved in 50 ml of n-heptane at room temperature. TO Then, HCl gas was bubbled through the solution, producing a precipitate. HCl gas was added until it was not observed more precipitation. The resulting grout is then stirred at room temperature for 0.5 hours. The product was isolated by filtration, washed with 10 ml of n-heptane and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.75 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 7

0.3 g of Cinacalcet base was stirred in 6 ml of n-heptane at room temperature. Then it added 3 ml of 1 N HCl in one portion, producing a precipitation immediate. The resulting mixture was stirred at room temperature, it is say, at between about 20 ° C and about 25 ° C, during the night. The product was isolated by filtration, washed with 4 ml of n-heptane and dried at 50 ° C in a vacuum oven for 25 hours, producing 0.3 g of the crystalline Form I of the Cinacalcet hydrochloride.

Example 8

0.8 g of Cinacalcet base was dissolved in 50 ml of n-hexane at room temperature. Then HCl gas was bubbled through the solution, producing a precipitate. The HCl gas was added until it was not observed additional precipitation The resulting slurry was stirred at room temperature for 20 minutes. The product was isolated by filtration, washed with 10 ml of n-hexane and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.76 g of Cinacalcet hydrochloride Form I crystalline.

Example 9

0.85 g of Cinacalcet base was dissolved in 50 ml of cyclohexane at room temperature. Then it was done bubble HCl gas through the solution until a oily precipitate The mixture was then stirred at temperature ambient for 16 hours. The product obtained was isolated by filtration and dried at 50 ° C in a vacuum oven for 24 hours, yielding 0.54 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 10

0.75 g of Cinacalcet base was dissolved in 50 ml of diethyl ether at room temperature. Then it was done bubble HCl gas through the solution in order to obtain a precipitate. The resulting slurry was stirred at room temperature during 20 minutes. The product was isolated by filtration, washed with 10 ml of diethyl ether and dried at 50 ° C in a vacuum oven for 16 hours, producing 0.55 g of the crystalline Form I of the Cinacalcet hydrochloride.

Example 11

0.3 g of Cinacalcet base was dissolved in 6 ml of diethyl ether at room temperature, that is, between about 20 ° C and about 25 ° C. then it 3 ml of 1N HCl in a single portion was added to the solution, producing a precipitation immediately. The resulting grout is stirred at room temperature, that is, between about 20 ° C and about 25 ° C, overnight. The resulting product is isolated by filtration, washed with 5 ml of diethyl ether and dried to 50 ° C in a vacuum oven for 24 hours, producing 0.26 g of the Cinacalcet hydrochloride form I crystalline.

Example 12

0.72 g of Cinacalcet base in 50 ml was stirred of water at room temperature. Then it was bubbled HCl gas through the solution to obtain a precipitate. The resulting slurry was stirred at room temperature for 2.5 hours. The product was isolated by filtration, washed with 20 ml of water, dried at 50 ° C in a vacuum oven for 19 hours, yielding 0.56 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 13

1.0 g of base was partially dissolved Cinacalcet in 30 ml of n-pentane at temperature ambient. Then HCl gas was bubbled through the dissolution, producing a precipitate. The HCl gas was added until that no additional precipitation was observed. The resulting grout is stirred at room temperature for 0.5 hours. The product s isolated by filtration, washed twice with 25 ml of n-pentane and dried at 50 ° C in a vacuum oven for 16 hours, producing 0.87 g of the crystalline Form I of the Cinacalcet hydrochloride.

Example 14

2.2 g of Cinacalcet base was dissolved in 2 ml of acetone at room temperature. Then 10 ml was added of 1N HCl in one portion and the mixture was stirred at room temperature for 1 hour, producing a precipitate. The product was isolated by filtration, washed with 10 ml of water and dried at 50 ° C in a vacuum oven for 24 hours, producing 1.75 g of Form I Cinacalcet hydrochloride crystal. Purity: 99.9% area HPLC

Example 15

2.0 g of Cinacalcet base was dissolved in acetone (10 ml). Then HCl gas (0.3 g; 1.5 eq.) Through dissolution. The solution obtained is evaporated under reduced pressure to dryness to obtain 2.1 g of Cinacalcet hydrochloride Form I crystalline.

Example 16

Cinacalcet base (2.0 g) was dissolved in acetone (4 ml) at room temperature. Then 1 N was added HCl (1.5 eq.) And water (40 ml) to the solution. The resulting mixture stirred at room temperature for 4 hours to obtain a precipitate. The product was isolated by filtration, washed with water (10 ml) and dried at 50 ° C in a vacuum oven for 24 hours to obtain 1.75 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 17

0.3 g of Cinacalcet base was dissolved in 4 ml of isobutyl acetate at room temperature, that is, between about 20 ° C and about 25 ° C. then it added 2 ml of 1 N HCl in one portion and the mixture was stirred at room temperature overnight, producing a precipitate. The product was isolated by filtration, washed with 5 ml of acetate isobutyl and dried at 50 ° C in a vacuum oven for 24 hours, producing 0.12 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 18

0.49 g of Cinacalcet base was dissolved in 10 ml of toluene at room temperature, that is to say between about 20 ° C and about 25 ° C. Then it 2 ml of 1 N HCl was added in one portion and the resulting mixture was stirred at room temperature overnight, producing a precipitate. The product was isolated by filtration, washed with 10 ml. of toluene and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.02 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 19

1.2 g of Cinacalcet base was stirred in 20 ml of MTBE at room temperature. Then 10 ml of 1 N was added HCl in one serving. Precipitation occurred immediately. Mix It was stirred at room temperature for 4 hours. The product is isolated by filtration, washed with 5 ml of MTBE and dried at 50 ° C in a vacuum oven for 16.5 hours, producing 0.58 g of the Form I crystalline of Cinacalcet hydrochloride.

Example 20

0.83 g of Cinacalcet base was dissolved in 50 ml of MTBE at room temperature. It was then bubbled HCl gas through the solution. The solution was stirred at room temperature for 0.5 hours to obtain a precipitate. The product was isolated by filtration, washed with 8 ml of MTBE and dried at 50 ° C in a vacuum oven for 15 hours, producing 0.5 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 21

Base CNC (3.15 g) was dissolved in MTBE (15 vol.) at room temperature. HCl gas was bubbled through the solution obtained, producing a precipitate. The HCl gas is added until no additional precipitation was observed. Grout stirred at room temperature for an additional 1 hour. He product was isolated by filtration, washed with MTBE (2 x 2 ml) and dried at 50 ° C in a vacuum oven for 16 hours to obtain 1.93 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 22

Base CNC (3.0 g) was dissolved in MTBE (20 vol.) At room temperature. HCl gas was bubbled through the solution obtained, producing a precipitate. The HCl gas is added in until no additional precipitation was observed. The slurry was stirred at room temperature for an additional 1 hour. He product was isolated by filtration, washed with MTBE (2 x 2 ml) and dried at 50 ° C in a vacuum oven for 15 hours to obtain 2.08 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 23

0.75 g of Cinacalcet base was dissolved in 3 ml of absolute ethanol at room temperature. Then it added 14 ml of 1N HCl dropwise to the solution and the mixture resulting was stirred at room temperature for 3.5 hours to Get a precipitate. The product was isolated by filtration, washed with 2 ml of water and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.5 g of the crystalline Form I hydrochloride of Cinacalcet

Example 24

5 g of base CNC was dissolved in 5 ml of DMF at room temperature. Then 50 was added to the solution 1 N HCl ml dropwise over a period of 4 minutes. The resulting slurry was stirred at room temperature for 3 hours. The product was isolated by vacuum filtration, washed with 2 x 10 ml of water and dried at 50 ° C for 14.5 hours to obtain 4.13 g of Cinacalcet hydrochloride Form I crystalline.

Example 25

5 g of base CNC was dissolved in 5 ml of DMSO at room temperature. Then 50 was added to the solution ml of 1 N HCl dropwise over a period of 10 minutes. The resulting slurry was stirred at room temperature for 3 hours. The product was isolated by vacuum filtration, washed with 2 x 15 ml of water and dried at 50 ° C for 14.5 hours to obtain 4.11 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 26

5 g of base CNC was dissolved in 5 ml of NMP at room temperature. Then 50 ml of 1 N HCl was added drop dropwise over a period of 8 minutes. The resulting grout is stirred at room temperature for 3 hours. The product was isolated by vacuum filtration, washed with 2 x 10 ml of water and dried at 50 ° C for 14.5 hours to obtain 4.31 g of crystalline Form I of Cinacalcet hydrochloride.

Example 27

5 g of base CNC was dissolved in 5 ml of acetonitrile at room temperature. Then 50 ml was added 1 N CHl dropwise over a period of 7 minutes. Grout The resulting was stirred at room temperature for 5 hours. He product was isolated by vacuum filtration, washed with 2 x 10 ml of water and dried at 50 ° C for 14.5 hours to obtain 4.30 g of the Cinacalcet hydrochloride form I crystalline.

Example 28

5 g of base CNC was dissolved in 5 ml of dimethylacetamide at room temperature. It was then added to the 50 ml solution of 1 N HCl dropwise over a period of 12 minutes The resulting slurry was stirred at room temperature During 4 hours. The product was isolated by vacuum filtration, it was washed with 2 x 10 ml of water and dried at 50 ° C for 14.5 hours to obtain 4.53 g of the crystalline Form I of the hydrochloride of Cinacalcet

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Preparation of Form I crystalline hydrochloride Cinacalcet from Cinacalcet hydrochloride by solvent / anti-solvent procedure Example 29

0.3 g of Cinacalcet hydrochloride was dissolved in 7 ml of acetone at room temperature. Then it 35 ml of n-heptane was added in one portion and stirred the mixture at room temperature for 16 hours. The product is leaked by filtration, washed with 4 ml of n-heptane and dried at 50 ° C in a vacuum oven for 23 hours, producing 0.26 g of the crystalline Form I of the Cinacalcet hydrochloride.

Example 30

0.3 g of Cinacalcet hydrochloride was dissolved in 9 ml of acetone at room temperature. Then it 45 ml of diethyl ether was added in one portion and the mixture was stirred for 16 hours at room temperature. The product was isolated by filtration and dried at 50 ° C in a vacuum oven for 23 hours, producing 0.18 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 31

1.0 g of Cinacalcet hydrochloride was dissolved in 18 ml of acetone at room temperature. The solution obtained 300 ml of diethyl ether was added dropwise and stirred at room temperature for 2 hours. The product was isolated by filtration and dried at 50 ° C in a vacuum oven for 16 hours, yielding 0.53 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 32

0.3 g of Cinacalcet hydrochloride was dissolved in 9 ml of acetone at room temperature. Then it was added 50 ml of n-hexane in one portion and the Mix at room temperature for 5 hours. The product was isolated by filtration, washed with 2 ml of n-hexane and dried at 50 ° C in a vacuum oven for 16 hours, producing 0.3 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 33

0.3 g of Cinacalcet hydrochloride was dissolved in 9 ml of acetone at room temperature. Then it was added in one portion 70 ml of MTBE and the mixture was stirred at temperature ambient for 16 hours. The product was isolated by filtration and was dried at 50 ° C in a vacuum oven for 24 hours, producing 0.16 g of the crystalline Form I of Cinacalcet hydrochloride.

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Example 34

0.3 g of Cinacalcet hydrochloride was dissolved in 7 ml of acetone at room temperature. Then it 50 ml of cyclohexane was added in one portion and the mixture was stirred at room temperature for 4 hours. The product was isolated by filtration, washed with 4 ml of cyclohexane and dried at 50 ° C in a vacuum oven for 16 hours, producing 0.23 g of Form I Cinacalcet hydrochloride crystal.

Example 35

0.3 g of Cinacalcet hydrochloride was dissolved in 9 ml of acetone at room temperature. Then it 50 ml of n-pentane was added in one portion and stirred the mixture at room temperature for 4 hours. The product is isolated by filtration, washed with 3 ml of n-pentane and dried at 50 ° C in a vacuum oven for 16 hours, producing 0.35 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 36

0.36 g of Cinacalcet hydrochloride was dissolved in 2 ml of absolute ethanol at room temperature. Then, 15 ml of n-pentane was added dropwise and stirred the mixture at room temperature for 2.5 hours. The product is isolated by filtration, washed with 2 ml of n-pentane and dried at 50 ° C in a vacuum oven for 18 hours, producing 0.24 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 37

0.5 g of Cinacalcet hydrochloride was dissolved in 3 ml of absolute ethanol at room temperature. Dissolution obtained was added dropwise to 300 ml of n-pentane and the mixture was stirred at room temperature for 10 minutes. He product was isolated by filtration and dried at 50 ° C in an oven empty for 17.5 hours, producing 0.3 g of Form I Cinacalcet hydrochloride crystal.

Example 38

0.3 g of Cinacalcet hydrochloride was dissolved in 2 ml of absolute ethanol at room temperature. Then, 15 ml of n-pentane was added dropwise and stirred the mixture at room temperature for 3 hours. The product is isolated by filtration, washed with 2 ml of n-pentane and dried at 50 ° C in a vacuum oven for 18 hours, producing 0.18 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 39

0.3 g of Cinacalcet hydrochloride was dissolved in 2 ml of absolute ethanol at room temperature. Then 15 ml of MTBE was added dropwise and the mixture was stirred for 3 hours at room temperature. The product was isolated by filtration and dried at 50 ° C in a vacuum oven for 18 hours, producing 0.16 g of the crystalline Form I of Cinacalcet hydrochloride.

Example 40

0.3 g of Cinacalcet hydrochloride was dissolved in 2 ml of absolute ethanol at room temperature. Then, 15 ml of water was added dropwise and the mixture was stirred at room temperature for 3.5 hours. The product was isolated by filtration, washed with 5 ml of water and dried at 50 ° C in an oven vacuum for 18 hours, producing 0.19 g of crystalline Form I of Cinacalcet hydrochloride.

Example 41

0.3 g of Cinacalcet hydrochloride was dissolved in 2 ml of absolute ethanol at room temperature. Then, 15 ml of diethyl ether was added dropwise and the mixture was stirred at room temperature for 16 hours. The product was isolated by filtration and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.14 g of the crystalline Form I of the hydrochloride of Cinacalcet

Example 42

0.24 g of Cinacalcet hydrochloride was dissolved in 1.5 ml of absolute ethanol at room temperature. Then,  15 ml of n-hexane was added dropwise and stirred the mixture at room temperature for 16 hours. The product is isolated by filtration and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.23 g of the crystalline Form I of the Cinacalcet hydrochloride.

Example 43

0.4 g of Cinacalcet hydrochloride was dissolved in 13 ml of IPA at room temperature. Then it was added 50 ml of n-hexane in one portion and the Mix at room temperature for 6.5 hours. The product is isolated by filtration and dried at 50 ° C in a vacuum oven for 16 hours, producing 0.05 g of the crystalline Form I of the Cinacalcet hydrochloride.

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Example 44

0.3 g of Cinacalcet hydrochloride was dissolved in 10 ml of IPA at room temperature. Then it was added 50 ml of n-pentane in one portion and the Mix at room temperature for 2.5 hours. The product is isolated by filtration and dried at 50 ° C in a vacuum oven for 17.5 hours, producing 0.1 g of the crystalline Form I of the Cinacalcet hydrochloride.

Example 45

0.64 g of Cinacalcet hydrochloride was dissolved in 2 ml of methanol at room temperature. Then it added 15 ml of water in one portion and the mixture was stirred at room temperature for 50 minutes. The product was isolated by filtration and dried at 50 ° C in a vacuum oven for 17 hours, producing 0.4 g of the crystalline Form I hydrochloride of Cinacalcet

While it is clear that the present invention disclosed herein is well calculated for achieve the above mentioned objective, it will be appreciated that subject matter experts can design multiple modifications and embodiments. Therefore, it is intended that attached claims include such modifications and forms of embodiment within the scope of the present invention.

Claims (21)

1. Procedure for the preparation of a crystalline form of Cinacalcet hydrochloride, in which the crystalline form of Cinacalcet hydrochloride is characterized in that it has peaks at 13.9, 19.0, 21.3, 25.5 \ pm 0.2 ° 2?, the procedure comprising:

to.

provide a solution of Cinacalcet base in a solvent in which Cinacalcet hydrochloride has low solubility;

b.

acidify the solution with acid hydrochloric in order to obtain a reaction mixture;

C.

keep the reaction mixture to obtain a precipitate; Y

d.

recover the crystalline form I of precipitated Cinacalcet hydrochloride;

in which the solvent is selected from the group consisting of water, a ketone C 3 -C 6, aliphatic or aromatic hydrocarbon C 5 -C 8, ester C 3 -C 6 different from ethyl acetate, a C 2 -C 5 alcohol, an ether C 2 -C 5, acetonitrile, DMAc, DMF, DMSO, NMP and mixtures thereof. 2. Method according to claim 1, in which the solvent is selected from the group constituted by water, acetone, n-heptane, n-pentane, diethyl ether, isobutyl acetate, toluene, MTBE, ethanol, DMF, DMSO, NMP, acetonitrile, DMAc, n-pentane, n-hexane and cyclohexane, more preferably the solvent is selected from the group consisting of water, toluene, acetone and MTBE. 3. Procedure according to any of the claims 1 to 2, wherein the hydrochloric acid is gaseous or aqueous. 4. Method according to claim 3, which it also comprises acidifying the solution with hydrochloric acid gas until no additional precipitation occurs. 5. Procedure according to any of the claims 1 to 4, further comprising maintaining the mixture of reaction for between about 20 minutes and about 72 hours 6. Procedure according to any of the claims 1 to 5, further comprising filtering, washing and drying the precipitate to recover Cinacalcet hydrochloride. 7. Method according to claim 6, which it also comprises drying the precipitate at a temperature comprised between about 45 ° C and about 55 ° C under pressure reduced 8. Method of preparing a crystalline form of Cinacalcet hydrochloride, in which Cinacalcet hydrochloride is characterized in that it exhibits dust XRD peaks at 13.9, 19.0, 21.3, 25.5, ± 0.2 ° 2?, The procedure comprising:

to.

providing a slurry of amorphous Cinacalcet hydrochloride, characterized in that it has an XRD diffractogram, as described in Figure 4, in a solvent selected from the group consisting of water, MTBE and C 5 -C 8 alkanes;

b.

keep the grout at a temperature between the ambient temperature and the temperature of reflux for a period between 2 and 30 hours; Y

C.

recover the crystalline form of Cinacalcet hydrochloride.

9. Method according to claim 8, in which the solvent is water, MTBE or n-hexane. 10. Procedure according to any of the claims 8 and 9, wherein the solvent is used in a amount between about 5 and about 25 ml per gram of amorphous Cinacalcet hydrochloride. 11. Procedure according to any of the claims 8 to 10, wherein the slurry is maintained for at least 2 hours, preferably the grout is maintained for about 2 and about 24 hours. 12. Procedure according to any of the claims 8 to 11, further comprising filtering, washing and drying  the slurry in order to recover the hydrochloride from Cinacalcet 13. Method according to claim 12, which also includes drying the filtered and washed grout, under pressure reduced, at a temperature between approximately 40 ° C and approximately 60 ° C, preferably at a temperature comprised between about 45 ° C and about 50 ° C.

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14. Procedure according to any of the claims 12 and 13, further comprising drying the slurry filtered and washed for at least 5 hours, preferably for between about 7 and about 24 hours. 15. Procedure for the preparation of the crystalline Form I of Cinacalcet hydrochloride, in which Cinacalcet hydrochloride is characterized in that it has powder XRD peaks at 13.9, 19.0, 21.3, 25.5 , ± 0.2 ° 2?, comprising:

to.

provide a solution of Cinacalcet hydrochloride in a solvent selected from ketone C 3 -6, linear or branched alcohol C 1 -C 5 and mixtures thereof;

b.

combine the solution with a anti-solvent;

C.

keep the solution to get a precipitate; Y

d.

recover crystalline form I from Cinacalcet hydrochloride.

16. Method according to claim 15, in which the solvent is selected from the group consisting of acetone, ethanol, IPA and methanol. 17. Procedure according to any of the claims 15 to 16, wherein the anti-solvent is one in the that Cinacalcet hydrochloride is substantially insoluble, preferably the solvent is selected from the group consisting of water, a cyclic or non-cyclic hydrocarbon C 5 -C 8, an aliphatic or branched ether C 2 -C 5 and mixtures thereof, more preferably, the solvent is selected from the group consisting of water, n-heptane, n-hexane, n-pentane, diethyl ether, MTBE, cyclohexane and mixtures thereof. 18. Procedure according to any of the claims 15 to 17, wherein the anti-solvent is added in an amount between approximately 4 volumes and approximately 100 volumes of solution. 19. Procedure according to any of the claims 15 to 18, further comprising maintaining the solution to obtain a precipitate by stirring during at least 10 minutes, preferably for a period between approximately 10 minutes and approximately 24 hours. 20. Procedure according to any of the claims 15 to 19, further comprising filtering, washing and Dry the precipitate in order to recover the hydrochloride from Cinacalcet 21. Procedure according to any of the claims 15 to 20, further comprising drying the precipitate at a temperature between approximately 45 ° C and approximately 55 ° C under reduced pressure.